Aging

Essential Fatty Acids and Biological Aging

Abstract and Commentary

By Donald J. Brown, ND, Managing Director, Natural Product Research Consultants, Seattle, WA. Dr. Brown reports no financial relationships relevant to this field of study.

Synopsis: Telomeres are present at the end of chromosomes and help prevent them from degradation. Shortening of telomeres can be caused by inflammation and oxidative stress and has been linked to age-related disease and earlier mortality in humans. This study suggests that telomere length may be influenced by n-6:n-3 PUFA plasma ratios.

Source: Kiecolt-Glaser JK, et al. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun 2012; doi: 10.1016/j.bbi.2012.09.004. [Epub ahead of print].

In a randomized, double-blind, placebo-controlled trial, 106 men and women (ages 40-85) were recruited from an earlier trial studying the effects of omega-3 polyunsaturated fatty acid (PUFA) supplementation on inflammatory markers in healthy middle-aged and older adults.1 After a single-blind, 7-day, placebo run-in period, subjects were randomized to receive either 2.5 g/day of n-3 PUFA (n = 35); 1.25 g/day of n-PUFA (n = 40); or placebo (n = 31) for 4 months. The fish oil used in the study provided a 7:1 ratio of EPA:DHA. The researchers state that this ratio was used “because of evidence that EPA has relatively stronger anti-inflammatory and antidepressant effects than DHA.” The placebo was a mixture of palm, olive, soy, and canola oils, as well as cocoa butter, which approximated the saturated:monounsaturated:polyunsaturated ratio consumed by U.S. adults (37:42:21). Blood samples were drawn at baseline and 4 months to plasma fatty acids, F2-isoprostanes (a measure of oxidative stress), telomere length, and telomerase activity. Telomeres are the caps found at the ends of chromosomes and are essential for chromosomal stability and replication. Telomerase is an enzyme important for telomere formation, maintenance, and restoration.

At the end of 4 months, supplementation with the low-dose and high-dose n-3 PUFA led to a significantly lowered oxidative stress as measured by F2-isoprostanes compared to placebo (P = 0.02). The researchers chose this measure of oxidative stress because it “provides the most reliable index of in vivo stress when compared to other well-known biomarkers.” The estimated geometric long-F2-isoprostanes values were 15% lower in the two n-3 supplemented groups compared to placebo. The adjusted mean change in telomere length (expressed in base pairs [bp]) was an increase of 21 bp and 50 bp for the low-dose and high-dose groups, respectively, compared to a decrease of 43 bp for the placebo group. However, these differences did not reach statistical significance (P = 0.53 and P = 0.29 for the low-dose and high-dose groups, respectively). Telomere lengthening was observed in 54% of the high-dose group and 53% of the low-dose group, compared to 39% in the placebo group. These differences also were not statistically significant (P = 0.39 for both low- and high-dose groups). There was no difference between groups in telomerase activity. However, when analyzing based on n-6:n-3 PUFA plasma ratios, telomere length was found to significantly increase with decreasing n-6:n-3 ratios (P = 0.02). A 1-unit decrease in n-6:n-3 was associated with an estimated 20 bp increase in telomere length.

Commentary

Telomeres and their binding proteins at the end of chromosomes prevent chromosomes from detrimental recombination and degradation.2 Telomerase maintains or lengthens telomeres by adding telomeric DNA to shortened telomeres.3 Telomere length has been linked and likely regulated by exposure to proinflammatory cytokines and oxidative stress.4,5 Inflammation triggers T-cell proliferation, a known cause of telomere shortening. In vitro studies have found that oxidative stress stimulates telomere erosion during cell replication.4

Studies in mice have suggested that there is a causal effect of telomerase deficiency and telomere shortening in cellular health, premature aging, and mortality.6,7 Human studies also have suggested a link between shorter telomeres and age-related disease (e.g., heart disease and cancer) and earlier mortality.8,9 Depression and chronic stress also have been associated with shorter telomeres.10,11 It should be noted that depression and chronic stress boost inflammation and that there is a link between lower n-3 PUFA plasma ratios and depression.12

Although telomeres shorten with aging, shortening is not inevitable and may be influenced by certain nutrients found in both food and supplements. Based on their earlier study that found n-3 PUFA intake reduced inflammation,1 the researchers speculated that blood levels of PUFAs (primarily n-3 PUFAs) may be one of the factors that can prevent telomere shortening over time. In the Heart and Soul Study, which followed 608 people with stable coronary heart disease for 5 years, slower telomere attrition was predicted by higher baseline levels of EPA and DHA.13 Although preliminary in nature, the results of this new study suggest that the best predictor may be n-6:n-3 PUFA plasma ratios. The implication in effecting this ratio with diet or supplements is to decrease dietary sources of n-6 PUFAs, and increase dietary or supplemental sources of n-3 PUFAs. It is hoped that larger trials will follow to show this connection more clearly. Future trials also should measure n-6 and n-3 PUFAs in red blood cells (RBC) in addition to plasma levels as circulating PUFA levels reflect the interplay between dietary intake, absorption, and metabolism and are sometimes not strongly correlated with dietary intake.14 RBC PUFA levels reflect longer-term PUFA consumption as the turnover is slower than plasma levels.15

A 2009 study published in the American Journal of Clinical Nutrition found that multivitamin use was associated with longer telomere length among 586 women, ages 35-74 years.16 Compared with nonusers, the relative telomere length of leukocyte DNA was on average 5.1% longer (P = 0.002). Also notable was the finding that higher intake of vitamins C and E from foods also was associated with longer telomeres.

Although the association explored in this study is preliminary, it provides yet another reason to consume n-3 PUFAs. To approximate the amounts used in the study, one would have to consume one serving of fish per day or approximate the same dose of EPA and DHA through fish oil supplements. With much of the “anti-aging” promise of antioxidant foods and supplements as well as essential fatty acids seeming somewhat speculative, the science of measuring telomeres and telomerase activity may provide a new way to measure the ability of these nutrients to truly slow biological aging.

References

1. Kiecolt-Glaser JK, et al. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: A randomized controlled trial. Brain Behav Immun 2012;26:988-995.

2. Blasco MA. Telomeres and human disease: Ageing, cancer and beyond. Nat Rev Genet 2005;6:611-622.

3. Chan SW, Blackburn EH. Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol Cell 2003;11:1379-1387.

4. Aviv A. Telomeres and human somatic fitness. J Gerontol A Biol Sci Med Sci 2006;61:871-873.

5. Carrero JJ, et al. Telomere attrition is associated with inflammation, low fetuin-a levels and high mortality in prevalent hemodialysis patients. J Intern Med 2008;263:302-312.

6. Bernardes de Jesus B, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 2012;4:691-704.

7. Jaskelioff M, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469:102-106.

8. Brouilette S, et al. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol 2003;23:842-846.

9. Kimura M, et al. Telomere length and mortality: A study of leukocytes in elderly Dutch twins. Am J Epidemiol 2008;167:799-806.

10. Epel ES, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 2004;101:17312-17315.

11. Wolkowitz OM, et al. Depression gets old fast: Do stress and depression accelerate cell aging? Depress Anxiety 2010;27:327-338.

12. Appleton KM, et al. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010;91:757-770.

13. Farzaneh-Far R, et al. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 2010;303:250-257.

14. Fusconi E, et al. Relationship between plasma fatty acid composition and diet over previous years in the Italian centers for the European Perspective Investigation into Cancer and Nutrition (EPIC). Tumori 2003;89:624-635.

15. Harris WS. The omega-3 index: From biomarker to risk marker to risk factor. Curr Atheroscler Rep 2009;11:411-417.

16. Xu Q, et al. Multivitamin use and telomere length in women. Am J Clin Nutr 2009;89:1857-1863.